The ability of the immune response to protect the host from pathogens without causing damage depends on a dynamic system that can tightly regulate its responses. Recently, a T lymphocyte subset, defined as CD4+CD25 v (Treg cells), was shown to suppress excessive T cell activation. Little is known about the phenotypic features and mechanisms of function of Treg cells. The role of Treg cells during chronic infections such as HIV-1 infection, which causes hyperactivation of immune system, is also not known. A major obstacle in defining the role of Treg cells in human diseases with chronic immune activation is difficulty in discriminating this subset from recently activated T cells. The main goal of this proposal is to develop more advanced phenotypic and functional profile of human Treg cells in order to establish their role in HIV infection. To achieve this we propose: 1) To better define cell-surface phenotype and effector functions of human Treg cells. 2) To discover new molecules exclusively expressed on Treg cells by innovative techniques to generate monoclonal antibodies and gene-expression analysis. 3) To determine the relative contribution of candidate molecules in suppressive function of Treg cells. 4) To use these tools to establish whether Treg cells can have a potential role during the HIV infection and can be identified in infected individuals. We anticipate that the proposed studies will yield a highly significant framework to understand the molecular basis of Treg suppression and their potential contribution to HIV pathogenesis. The tools and knowledge gained from these studies could also have far reaching impact in developing novel strategies to manipulate the regulatory arm of immune system. Enhancing Treg cell function during unwanted immune activation such as autoimmunity and transplantation might prove as a useful treatment, whereas downregulation of these cells might be beneficial to increase the efficacy of potential vaccines to HIV and other pathogens.